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Calcific aortic valve disease is the most common indication for surgical valve replacement in the United States. However, the number of patients that go undiagnosed is staggering (1). During the past decade, the risk factors and emerging methods of diagnosis are increasing rapidly as novel therapeutic treatment modalities are evolving in the 21st century (2). In the paper by Linefsky et al. (3) in this issue of the Journal, the investigators performed a stringent analysis of the CHS (Cardiovascular Health Study) population to determine if high-normal serum phosphate levels are associated with 3 areas known to calcify with age: aortic valve leaflet, mitral annulus, and aortic annulus. In this study, the researchers demonstrated that high-normal serum phosphate levels were increased in the aortic valve leaflet (54%), mitral annulus (39%), and aortic annulus (44%) without an association with serum calcium, parathyroid hormone, and 25-hydroxyvitamin D levels. This finding correlates nicely with the growing scientific evidence in the past 10 years demonstrating that this disease process is an active mineralization process (3).

The presence of calcification in the aortic valve is responsible for valve stenosis (4). Severe aortic stenosis can result in symptomatic chest pain, as well as syncope and congestive heart failure in patients with severe aortic valve stenosis (5). For years, aortic valve stenosis was thought to be a degenerative process. However, the pathological lesions of calcified aortic valves indicate the presence of complex calcification in these tissues and bone formation in the aortic valve (6–9). Until recently, the etiology of valvular heart disease has been thought to be a degenerative process related to the passive accumulation of calcium binding to the surface of the valve leaflet. Recent descriptive studies have demonstrated the critical features of aortic valve calcification, including osteoblast expression, bone cell phenotypes, cell proliferation, and atherosclerosis (6,8,10,11). These studies have defined the biochemical and histological characterization of osteoblast-like bone formation in these valve lesions.

Stewart et al. (12) and Otto et al. (13) initially described the risk factors for calcific aortic stenosis identified in the CHS. The investigators examined 5,621 patients older than 65 years and found by Doppler echocardiography that the prevalence of aortic valve sclerosis was 29% and aortic valve stenosis was 2% in this population. The investigators demonstrated that the clinical risk factors important for the development of atherosclerosis are also independent risk factors for aortic valve stenosis, including age, male sex, height (inverse relationship), history of hypertension, smoking, and elevated serum levels of lipoprotein(a) and low-density lipoprotein (12). In this study by Linefsky et al. (3), the investigators evaluated the 1992 or 1993 examinations from the CHS population-based cohort study for an association of phosphate levels in the areas well known to calcify, including the aortic valve leaflet, mitral annulus, and aortic annulus. Serum phosphate, calcium, and parathyroid hormone levels were measured. Lipid levels, glomerular filtration rate, blood glucose levels, cystatin C levels, and blood pressure were also measured. The presence of calcium was identified using 2-dimensional echocardiography.

Interestingly, although the serum phosphate levels correlated with cardiovascular calcification, they were also directly proportional to the low-density lipoprotein levels and inversely proportional to the glomerular filtration rate. The most common cause of elevated levels of serum phosphate is reduced urinary excretion with reduced renal function (14). Understanding the spectrum of chronic renal disease and cardiovascular calcification may contribute to the findings of this study. In vivo models of vascular (15) and valvular calcification (16) are evolving to test this hypothesis at the cellular level. Figure 1 demonstrates the paradox for bone-cardiovascular calcification. This ongoing paradox between cardiovascular calcification and osteoporosis has been under intense investigation (17) for the past 15 years. This study provides the next step in our understanding of this paradox and the need for continued studies for patients with both cardiovascular calcification and osteoporosis. Identification of early valve sclerosis with a stethoscope, multimodality imaging, and measurement of traditional cardiovascular risk factors may help to identify early preclinical disease in the heart and vasculature to risk-stratify patients and modify cardiovascular risk factors (18) in this patient population.

The figure demonstrates the connection between mineral and cardiovascular calcification in the development of bone formation in the heart. LDL = low-density lipoprotein.

Footnotes

Dr. Rajamannan receives funding from the National Institutes of Health (5R01HL085591-04 and 3R01HL085591-02S1) and is an inventor on a patent for the use of statins in degeneration of aortic valve disease. This patent is owned by the Mayo Clinic, and Dr. Rajamannan does not receive any royalties from this patent.

↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

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